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Cellular Microbiology: Pathogen-Host Cell Molecular Interactions

Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis

James E. Kirby
James E. Kirby
Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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  • For correspondence: jekirby@bidmc.harvard.edu
DOI: 10.1128/IAI.72.1.430-439.2004
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ABSTRACT

Because of its ease of dispersal and high lethality, Bacillus anthracis is one of the most feared biowarfare agents. A better understanding of anthrax pathogenesis is urgently needed to develop new therapies for systemic disease that is relatively unresponsive to antibiotics. Although experimental evidence has implicated a role for macrophages in anthrax pathogenesis, clinical and pathological observations suggest that a direct insult to the host vasculature may also be important. Two bacterial toxins, lethal toxin and edema toxin, are believed to mediate the clinical sequelae of anthrax. Here, I examined whether these toxins are directly toxic to endothelial cells, the cell type that lines the interior of blood vessels. I show for the first time that lethal toxin but not edema toxin reduces the viability of cultured human endothelial cells and induces caspase-dependent endothelial apoptosis. In addition, this toxicity affects both microvascular and large vessel endothelial cells as well as endothelial cells that have differentiated into tubules within a type I collagen extracellular matrix. Finally, lethal toxin induces cleavage of mitogen-activated protein kinase kinases in endothelial cells and inhibits phosphorylation of ERK, p38, and JNK p46. Based on the contributions of these pathways to endothelial survival, I propose that lethal toxin-mediated cytotoxicity/apoptosis results primarily through inhibition of the ERK pathway. I also hypothesize that the observed endothelial toxicity contributes to vascular pathology and hemorrhage during systemic anthrax.

  • Copyright © 2004 American Society for Microbiology
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Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis
James E. Kirby
Infection and Immunity Dec 2003, 72 (1) 430-439; DOI: 10.1128/IAI.72.1.430-439.2004

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Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis
James E. Kirby
Infection and Immunity Dec 2003, 72 (1) 430-439; DOI: 10.1128/IAI.72.1.430-439.2004
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KEYWORDS

Antigens, Bacterial
apoptosis
bacterial toxins
endothelial cells

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